Putting the Efficacy of Candesartan Cilexetil Into Perspective

Home , Candesartan

Journal of Human Hypertension (2000) 14, Suppl 2, S33–S41  2000 Macmillan Publishers Ltd All rights reserved 0950-9240/00 $15.00 www.nature.com/jhh Putting the efﬁcacy of candesartan cilexetil into perspective: a review of new comparative data

JM Mallion and JP Baguet CHU Hoˆ pital Michallon, Me´decine Interne et Cardiologie, Grenoble, France

Candesartan is one of the first angiotensin II receptor tions that can be made between the AIIRAs in terms of antagonists (AIIRAs) to be developed. It binds tightly to their pharmacokinetic profiles, the antagonistic potency and dissociates slowly from the angiotensin subtype 1 of candesartan cilexetil at the AT1 receptor over 24 h (AT1) receptor in vitro. These binding characteristics dif- clearly differentiates it from other members of its class. fer from those of losartan, which demonstrates lower These differences are reflected in the antihypertensive affinity and faster dissociation from the AT1 receptor. efficacy and duration of action of candesartan in clini- Candesartan causes long-lasting antagonism of the vas- cal trials. cular contractile response to angiotensin II compared Journal of Human Hypertension (2000) 14, Suppl 2, S33– with irbesartan, losartan or the active metabolite of los- S41 artan – EXP-3174. While there are relatively few distinc-

Keywords: candesartan cilexetil; angiotensin II AT1-receptor antagonist; antihypertensive treatment; comparative efﬁcacy review

Introduction the basis of their improved oral bioavailability and 6 potency at the AT1 receptor (Figure 1). Since the Angiotensin II receptor antagonists (AIIRAs) rep- introduction of the prototype losartan in 1994, new resent an important new class of antihypertensive agents such as candesartan cilexetil, valsartan, agents which enable a more specific and complete irbesartan, telmisartan and eprosartan have been block of the renin-angiotensin system (RAS) com- made available. These agents have been shown to pared with angiotensin-converting enzyme (ACE) combine blood pressure-lowering efficacy – compa- inhibitors. The AIIRAs selectively block the angi- rable with ACE inhibitors and calcium channel otensin subtype 1 receptor (AT ), which mediates 1 blockers – with a tolerability profile comparable most of the known actions of angiotensin II. The development of AIIRAs has overcome some with placebo. In addition to, and perhaps inde- of the difficulties apparent with ACE inhibition. pendent of, their antihypertensive action, their Regardless of whether the angiotensin II is produced potent inhibition of the RAS is expected to bring by ACE or ACE-independent pathways, such as additional benefits for the management of heart tissue chymase, chymostatin-sensitive angiotensin failure and renal disease (associated with diabetes II-generating enzyme (CAGE), cathepsin G and mellitus). others,1,2 the AIIRAs cause a highly specific block When used once daily, either as monotherapy or of the angiotensin II at its receptor. Although ACE in combination with other antihypertensive agents, inhibitors are efficacious and have relatively few the AIIRAs are effective for the management side effects,3 the lack of specificity of ACE inhibition of patients with mild, moderate and severe hyper- results in a potentiation of endogenous kinins tension. As well-tolerated antihypertensive agents, (bradykinin and tachykinin) associated with class- the AIIRAs are important new tools for the primary specific side effects such as angioedema and dry prevention of cardiovascular morbidity and cough.4 mortality. In the early 1980s, Takeda Chemical Industries, This paper reviews new data, comparing the phar- Ltd5 described the first non-peptide derivatives macodynamics and clinical efficacy of candesartan angiotensin antagonists (CV-2198, CV-2973 and cilexetil with the other members of this new class. CV-2961), which were considered specific but weak While all of these drugs are highly selective for the antagonists at the AT1 receptor. These molecules AT1 receptor, there are important differences in their served as structural templates for the development pharmacology, pharmacokinetics and pharmacody- of a series of new compounds that were selected on namics that are reflected in their duration of antihypertensive effect. In particular, they differ in affinity constants, especially dissociation constants from the Correspondence: Professor JM Mallion, CHU Hoˆpital Michallon, receptor, antagonism characteristics and in vivo Me´decine Interne et Cardiologie, BP 217, 38043 Grenoble Cedex 09, France. Tel: + 33 476 76 54 40, Fax: + 33 476 76 55 59 pharmacodynamics. The comparative efficacy of candesartan JM Mallion and JP Baguet S34

Figure 1 Discovery and development of selective non-peptide angiotensin II receptor antagonists.

Differential preclinical pharmacology of artan was the most potent of the AIIRAs tested; AIIRAs potencies were candesartan у irbesartan Ͼ EXP- 3174 Ͼ eprosartan and valsartan. Receptor binding affinity and specificity Like all the AIIRAs in clinical development, candes- Antagonistic properties artan is a potent and selective AT1 receptor blocker. The angiotensin II-mediated vascular contractile Candesartan dose-dependently inhibited the in vitro responses in isolated rat portal vein and rabbit aorta binding of radiolabelled angiotensin II at the AT1 in the presence of AIIRAs have been investigated receptor in rabbit aorta but did not interact with the independently by a number of research groups.10– angiotensin subtype 2 (AT2) receptor in the bovine 15 These studies have found that while candesartan Ͼ cerebellum. Candesartan had a 10 000-fold higher (0.01–1 nM) produces a clear dose-dependent affinity for the AT1 receptor compared with the AT2 reduction in the maximal contractile response to 7 receptor. The affinity of candesartan for the AT1 angiotensin II (characteristic of insurmountable or receptor was 80 times greater than that of losartan non-competitive antagonism),15 losartan and epros- and 10 times greater than the active metabolite of artan are displaced from the AT1 receptor with 7 losartan, EXP-3174. In human resistance vessels, increasing doses of angiotensin II and cause parallel 8 candesartan is 1000 times as potent as losartan. shifts of the dose response without affecting the The comparative potency of the AIIRAs was maximal effect of angiotensin II (competitive or sur- further evaluated in human AT1 receptors, isolated mountable antagonism).10,11,14 Valsartan, irbesartan from a human heart cDNA library and transfected and EXP-3174 (the active metabolite of losartan) 9 into COS-7 cells. The inhibitory effects of EXP- exhibit mixed-type competitive (or surmountable) 3174, eprosartan, irbesartan, candesartan and valsar- and non-competitive (insurmountable) antagonism tan on [I125] angiotensin II receptor binding were 11,12 at the AT1 receptor; telmisartan exhibits insur- compared. The results (Table 1) showed that candes- mountable (non-competitive) but reversible inhibition to angiotensin II-induced contractions in iso- 13 Table 1 Inhibitory effects of various angiotensin II receptor antag- lated rabbit aortic tissue. onists on the specific binding of [I125] angiotensin II to the human The antagonistic properties of candesartan, irbes-

AT1 receptor artan, losartan and its active metabolite EXP-3174 were compared by Morsing and colleagues (Figure 16 Compound Inhibition IC50 (nM) 2). The investigations were conducted in isolated preparations of rat portal vein and rabbit thoracic Candesartan 3.0 aortic strips using concentrations of antagonists Irbesartan 8.0 equivalent to the (non-protein-bound) plasma con- EXP-3174 (active metabolite of losartan) 9.2 Eprosartan 53.0 centrations achieved with oral dosing. The study Valsartan 60.0 found similar concentration curves in both rabbit aorta and rat portal vein, which have different tissue 9 Data from Konishi et al. reserves of AT1 receptor. In rabbit aorta, increasing

Journal of Human Hypertension The comparative efﬁcacy of candesartan JM Mallion and JP Baguet S35

Figure 2 Angiotensin II-mediated contractile response in isolated rabbit aorta in the presence of (a) candesartan (0.003–1 nM), (b) irbesartan (1–100 nM), (c) losartan (1–100 nM) or (d) EXP-3174 (0.01–1 nM) over 90 min. Reprinted by permission of Elsevier Science from Morsing et al,16 American Journal of Hypertension 11: 37.  1998 by American Journal of Hypertension Ltd. doses of angiotensin II displaced irbesartan (1–100 experimental conditions with drugs such as irbesar- nM), losartan (1–100 nM) and its metabolite EXP- tan may reﬂect the rate of dissociation from the AT1 3174 (0.1–10 nM) from the AT1 receptor, resulting receptor. When experiments with irbesartan were in parallel shifts in the contractile responses to angi- repeated in isolated rabbit aortic strips after equilib- otensin II. Candesartan (0.03–1 nM) reduced the rium had been reached at 22 h after washout, irbes- maximum response to angiotensin II, causing a artan was shown to have competitive antagonism.16 characteristic non-parallel shift in the dose-response curve of angiotensin II. At 1 nM candesartan, the Kinetics at the AT receptor angiotensin II response was completely suppressed. 1 For irbesartan (100 nM), some degree of suppression Candesartan binds tightly to and dissociates slowly 17 of the angiotensin II response was also recorded at from the AT1 receptor in vitro. These binding the highest concentrations in rabbit aortic strips. characteristics differ from those of losartan, which It is likely that the mixed insurmountable and sur- demonstrates lower afﬁnity and faster dissociation 17,18 mountable antagonism observed under different from the AT1 receptor.

Journal of Human Hypertension The comparative efficacy of candesartan JM Mallion and JP Baguet S36 The duration of binding has been assessed in a antagonism was determined by recording DBP at the direct comparison of losartan, EXP-3174, irbesartan end of each angiotensin II infusion step and con- and candesartan in an isolated rat portal vein prep- structing individual dose-response curves using an 19 aration. The AIIRAs were introduced for a period Emax model. Both candesartan cilexetil and losartan of 1 h, after which the drugs were washed out. This reached peak concentrations after 4–5 h and were study showed that while the inhibitory effect of can- still detectable after 24 h. Concentration equivalents desartan persisted, the responses to angiotensin II at times у24 h were greater for candesartan cilexetil, rapidly returned to baseline values with irbesartan, with the maximum effect of candesartan cilexetil losartan or EXP-3174 after washout (Figure 3).19 being 1.65 and 1.94 times that of losartan after single Compared with irbesartan, losartan or EXP-3174, and repeated administration, respectively.21 The candesartan causes long-lasting antagonism of the antagonistic effect of candesartan increased by 1.33 vascular contractile response to angiotensin II.19 from day 1 to day 8, while no increase was observed for losartan. Thus, compared with losartan, candesartan cilexetil had an antagonistic effect on angiot- Differential pharmacodynamics ensin II that was markedly greater and longer last- AIIRAs block the blood pressure response to exogen- ing.21 This effect may be explained by its tighter ous angiotensin II in healthy volunteers, decrease binding and slower dissociation from the AT1 recep- baseline blood pressure in both normal and hyper- tor compared with losartan.22 tensive patients, produce a marked rise in plasma The antagonistic potency of candesartan cilexetil renin activity and endogenous angiotensin II and (4 mg, 8 mg and 16 mg) has also been compared with increase renal blood flow without altering glomeru- irbesartan (75 mg, 150 mg, 300 mg), losartan (25 mg, lar filtration rate. These effects are dose dependent, 50 mg, 100 mg) and valsartan (40 mg, 80 mg, 160 but their time course varies between the drugs mg) in humans.23 The dose-response curves of owing to pharmacokinetic and pharmacodynamic exogenous angiotensin II on DBP were evaluated at differences.20 regular time points up to 24 h after oral dosing with the AT1-receptor blockers. At each time point, the K or dose required to shift the dose-response curve Antagonism of the pressor response i two-fold to the right was calculated. The results The ability of candesartan cilexetil to antagonise showed that the Ki doses 24 h after oral adminis- angiotensin II was compared with losartan in heal- tration were 6 mg for candesartan, 123 mg for irbes- 21 thy volunteers in a double-blind cross-over study. artan and 93.5 mg for valsartan; however, a Ki value Twelve healthy volunteers received either candesar- for losartan could not be determined because of its tan cilexetil 8 mg or losartan 50 mg followed 48 h very small effect at this time point.23 These results later by daily doses for 6 days. Angiotensin II was confirm the findings from in vitro and in vivo studies infused at 3-min intervals at ascending doses from that candesartan has the highest direct angiotensin 0.17 to 20␮g/min or until diastolic blood pressure II antagonistic activity per mg at 24 h after dosing. (DBP) had increased by 25 mm Hg. Angiotensin II Renin stimulation

The efficacy of AT1-receptor antagonists is not only influenced by pharmacological and pharmacodynamic properties of the drug but also by patient- dependent factors: the more active the RAS, the stronger the antihypertensive response. In a human model in which mild sodium depletion in normotensive subjects was used to control renin status, the pharmacodynamic effects (fall in blood pressure and increase in active renin) of single oral doses of candesartan cilexetil (8 mg, 16 mg) and losartan (50 mg) were evaluated.24 This double-blind placebo-controlled study involved 16 healthy subjects pre- treated with a single dose of furosemide 40 mg. Mean blood pressure levels, plasma active renin, angiotensin I and angiotensin II levels were determined and correlated with the plasma candesartan and EXP-3174 levels over 24 h. The study found large inter-subject variability in the plasma pharmacokinetics of EXP-3174 whereas the inter-subject Figure 3 Antagonism of angiotensin II-mediated contractile variability for patients on candesartan was low. This response in isolated rat portal vein following incubation with (ș) was reflected in the greater inter-subject variability vehicle, (̆) candesartan (1 nM), (࡯) irbesartan (50 nM), () of plasma active renin levels with losartan com- losartan (30 nM) or (̅) EXP-3174 (1 nM) for 60 min then a pared with candesartan. Another primary endpoint washout period of 120 min. Reprinted by permission of Elsevier Science from Abrahamsson et al,19 American Journal of evaluated in this study was the duration of response Hypertension 11: 36.  1998 by American Journal of of AIIRAs. At 24 h, the inhibition of the RAS (as Hypertension Ltd. measured by AUC0–24h active renin levels) was sig-

Journal of Human Hypertension The comparative efficacy of candesartan JM Mallion and JP Baguet S37 Table 2 Plasma active renin levels (AR) in mild sodium-depleted desartan cilexetil (4–16 mg) produced a dose-depen- volunteers: a study comparing the effects of candesartan cilexetil dent reduction in both DBP and systolic blood press- (8–16 mg) with valsartan (80–160 mg) ure (SBP).36 On average, the placebo-corrected AR Candesartan Valsartan changes in sitting DBP from baseline were 4.5, 6 and 8 mm Hg with candesartan 4 mg, 8 mg and 16 mg, 8 mg 16 mg 80 mg 160 mg respectively, 24 h after dosing. The placebo-corrected blood pressure reductions were not affected 36 Baseline 60 59 57 55 by age, gender or baseline blood pressure. Other Peak 348 429 327 387 AIIRAs, valsartan, irbesartan and telmisartan, have 37–39 AUC0–24h 4556* 6543 3759* 4986* also shown dose-response curves but losartan, by contrast, displays a flat dose-response.40 P Ͻ 0.05 vs candesartan 16 mg. AR: plasma active renin levels (pg.h/ml); AUC: area under curve. Data from Azizi et al.25 Comparative clinical efficacy nificantly greater with candesartan cilexetil 16 mg The efficacy of candesartan cilexetil 8 mg once daily than with candesartan cilexetil 8 mg and losartan 50 was compared with losartan 50 mg once daily over mg (P Ͻ 0.05).24 36 h using ambulatory blood pressure monitoring in Further evaluation using the same experimental the clinic before and after 6 weeks of double-blind design found that candesartan cilexetil 16 mg achi- treatment.41 In total, 256 patients with mild-to-mod- eved a more prolonged and more potent blockade of erate (Ͻ95/115 mm Hg) essential hypertension were the RAS than valsartan 160 mg or 80 mg (P Ͻ 0.05) evaluated in an intention-to-treat analysis. The pri- (Table 2).25 The intra-individual active renin stimu- mary endpoints were the changes in mean blood lation was found to be highly reproducible and the pressure from baseline after 6 weeks of study treat- ratio of the drug AUC0–9h:active renin AUC0–9h was ment; blood pressure measurements were made at almost constant for both candesartan cilexetil and 0–24 h and 0–36 h after the last dose and during the valsartan at each dose and was correlated between day (07.00–22.00) and night (22.00–07.00). Com- drugs. pared with losartan 50 mg, the mean ambulatory While the pharmacodynamics of candesartan DBP changes from baseline were greater with cande- cilexetil clearly differentiate it from the other sartan cilexetil 8 mg at both 0–24 h (P Ͻ 0.05) and AIIRAs, pharmacokinetic parameters show few dif- 24–36 h (P Ͻ 0.01) after dosing. Furthermore, the ferences (Table 3).26–33 A better correlation for the magnitude of the ambulatory blood pressure prolonged and potent inhibition of the RAS by can- response was also significantly greater with candes- desartan may be its high affinity and slow dis- artan cilexetil (16 mg) compared with losartan 50 = = sociation from the AT1 receptor. mg for both day (P 0.018) and night (P 0.011) measurements, indicating significantly better peak Clinical experience and trough values for candesartan cilexetil. These results were confirmed by Andersson and Neld- In the clinic, candesartan cilexetil is administered ham41 who found that the placebo-corrected trough:- once daily and is completely and rapidly hydro- peak ratio for candesartan approached 1.0 (0.9–1.1) lysed during gastrointestinal absorption to candesar- compared with 0.7 for losartan, demonstrating tan, the active moiety.14 Once-daily candesartan improved 24-h blood pressure control with candes- cilexetil lowers the ambulatory blood pressure over artan compared with losartan in patients with mild- 24 h without affecting circadian variations in blood to-moderate hypertension. pressure.34 This reduction in arterial pressure is In another placebo-controlled randomised study, accompanied by a reduction in total peripheral the higher dose of losartan (100 mg) was compared resistance and renovascular resistance and an with candesartan cilexetil 16 mg over 8 weeks in increase in renal blood flow.35 268 patients with mild-to-moderate hypertension.42 In a meta-analysis of studies involving 1482 The study found that the differences in average patients with mild-to-moderate hypertension, can- changes in ambulatory blood pressure (from

Table 3 Pharmacokinetic proﬁle of the angiotensin II receptor antagonists

Drug Recommended Bioavailability (oral Plasma AUC Oral tmax Terminal plasma Elimination route of daily dose administration) reduced with food half-life 14C-labelled intake compounds (renal/biliary)

Candesartan25 8 or 16 mg (tablet) 42% No 3–5 h 9–13 h 33/68% Losartan26 50–100 mg (tablet) 33% No 1 h (3–5 h) 2 h (4–6 h) 30/65% Valsartan27–29 80–160 mg (capsule) 23% Yes 2–3 h 6.4–8.3 h 30/73% Irbesartan30 75–300 mg (tablet) 60–80% No 1–2 h 12–20 h 20/30% Eprosartan31 600–800 mg (2 tablets) 13% 25% reduction 1–3 h 5–7 h 10/90% Telmisartan32 40–80 mg (tablet) 43% 20% reduction ෂ1h ෂ24 h Ͻ1/Ͼ98%

Journal of Human Hypertension The comparative efﬁcacy of candesartan JM Mallion and JP Baguet S38

Figure 4 Mean change from baseline to week 8 in diastolic and systolic ambulatory blood pressure 0–36 h after dose; comparison of losartan 100 mg (ȦȦ) with candesartan cilexetil 16 mg (ۙۙ). Reprinted by permission of Elsevier Science from Lacourcie`re et al,42 American Journal of Hypertension 12: 143a.  1999 by American Journal of Hypertension Ltd.

baseline) over 36 h were significantly greater with Clinical efficacy vs usual treatment candesartan cilexetil 16 mg compared with losartan 100 mg, the differences between the drugs averaging Recent studies have also demonstrated comparable 5.8 mm Hg (SBP) and 3.5 mm Hg (DBP) (Figure 4).42 efficacy of candesartan cilexetil with other antihy- These differences became even more marked at 48 pertensive drugs such as the calcium antagonist h after dosing, when the effect of candesartan cilexe- amlodipine.46 Comparable efficacy with the ACE til was maintained but there was little or no remain- inhibitor enalapril has been demonstrated for all the ing effect of losartan. This study showed that the new AIIRAs including candesartan cilexetil,47–50 improved long-lasting efficacy of candesartan com- irbesartan,51 valsartan52 and telmisartan.53 pared with losartan becomes even more apparent for In three double-blind randomised studies of measurements beyond the 24-h dosing interval. patients with mild-to-moderate hypertension No direct comparative studies of candesartan (sitting DBP 95–114 mm Hg), candesartan cilexetil cilexetil with the other AIIRAs have been conducted exerted a reduction in blood pressure comparable to date. However, provisional evidence of mean pla- with enalapril but with a better side-effect pro- cebo-corrected reductions in DBP from two studies, file.47–49 one comparing losartan with irbesartan43 and the In a recent placebo-controlled, randomised study other comparing losartan with candesartan cilexe- by Malmqvist et al50 in 429 middle-aged hyperten- til,44 indicate that both the new AIIRAs are superior sive women, candesartan cilexetil (8–16 mg) low- to losartan (P Ͻ 0.01 for both) and exert a compara- ered both SBP and DBP more effectively than either ble reduction in DBP (−8.0 mm Hg with candesartan enalapril (10–20 mg) or hydrochlorothiazide (HCTZ) cilexetil; −6.8 mm Hg with irbesartan) (Figure (12.5–25 mg) after 6 and 12 weeks of treatment. The 5).41,43,45 difference in magnitude of response with candesar-

Figure 5 Placebo-corrected mean change from baseline in diastolic ambulatory pressures with angiotensin II receptor antagonists. Key: (CC) candesartan cilexetil, (IRB) irbesartan, (L) losartan, (V) valsartan. Data from Andersson and Neldam,41 Kassler-Taub et al43 and Hedner et al.45

Journal of Human Hypertension The comparative efficacy of candesartan JM Mallion and JP Baguet S39 tan was significant compared with both enalapril class. These differences are reflected in the antihy- (−19 mm Hg for candesartan cilexetil vs −13.5 pertensive efficacy and duration of action of candes- mm Hg for enalapril; P = 0.003) and HCTZ (−19 artan in clinical trials. mm Hg for candesartan vs −12.9 mm Hg for HCTZ; A number of clinical trials have shown that over P Ͻ 0.001). Furthermore, the study found that the therapeutic dose range studied, candesartan patients taking enalapril experienced significantly cilexetil 4–16 mg produces linear and dose-depen- more discomfort from dry cough than those taking dent reductions in both SBP and DBP that are unaf- candesartan cilexetil or HCTZ. These findings were fected by factors such as age or gender. The magni- confirmed in a study by Tanser et al54 who found tude of the blood pressure-lowering effect with that, in patients who experienced dry cough with candesartan is at least equivalent to several other enalapril, a switch to either candesartan cilexetil or widely used antihypertensive agents, and is perhaps placebo resulted in equal relief from this adverse more effective than losartan. Comparison of the event. mean placebo-corrected reduction in DBP across trials would seem to indicate the superior efficacy of both irbesartan and candesartan relative to losartan. Tolerability profile This has been confirmed in a direct comparative The tolerability of candesartan cilexetil has been study of once-daily candesartan cilexetil 8 mg and shown to be similar to that of placebo in an analysis 16 mg and losartan 50 mg, and more recently in a of more than 3000 patients and volunteers who comparison of candesartan cilexetil 16 mg and losar- received the drug at doses of up to 16 mg/day in tan 100 mg. Candesartan cilexetil 16 mg had a clini- Phase I–III trials.55 Total exposure to the drug was cally significantly greater blood pressure-lowering 854 patient-years. effect than losartan 50 mg after 24 h (P = 0.013). In double-blind clinical trials, patients with mild- Measures beyond 24 h after dosing show even to-moderate hypertension treated with candesartan greater differences between the efficacies of candes- cilexetil experienced an incidence of adverse events artan and losartan. Mean changes in ambulatory SBP that was comparable with that of placebo. Candesar- and DBP (from baseline) over 36 and 48 h were sig- tan cilexetil was equally well tolerated by women nificantly greater (P Ͻ 0.01) with candesartan cilexe- and men and by the young, elderly (у65 years) and til 16 mg than with losartan 100 mg. The clinically very elderly (у75 years),56 the latter being a popu- superior efficacy of candesartan in maintaining its lation that is often beset with a variety of toler- antihypertensive action over 24 h and up to 48 h ability problems. may provide an added benefit if patients miss a dose Candesartan cilexetil had no adverse metabolic of treatment. effects and was well tolerated in the long term (up In conclusion, the emerging clinical profile of can- to 1 year). Orthostatic or first-dose hypotensive desartan cilexetil provides evidence for its potent effects and rebound hypertension after cessation of and long-lasting blood pressure-lowering effect. The therapy were not associated with candesartan cilex- ability of candesartan cilexetil to effectively lower etil. Importantly, the incidence of cough was the blood pressure throughout the 24-h dose interval is same as with placebo (1.6 % for candesartan cilexe- consistent with its distinct receptor binding charac- til; 1.1% for placebo) and candesartan cilexetil had teristics within the AIIRAs, and its pharmacokinetic no apparent effect on plasma potassium concen- and pharmacodynamic characteristics confer flexi- trations.55 Consistent with its metabolic inactivity, bility in terms of its dosage administration. candesartan had no effect on glucose homeostasis or serum lipids when given to patients with hypertension and type II diabetes for 12 weeks.57 References

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